Regulation of radiation-induced apoptosis by NBS1 pathway

Abstract

Nijmegen breakage syndrome (NBS) is characterized by hyper-sensitivity to ionizing radiation, high frequency of chromosomal aberration, and high incidence of malignancy. NBS1, the underlying protein for NBS, form a complex with MRE11/RAD50 (M/R), and plays a crucial role in DNA repair processes by regulating the M/R activities and localization. NBS1 complex are also involved in DNA damage signaling, such as cell cycle checkpoint activation and apoptosis induction, through regulation of ATM activation and localization. Using hyper-recombinogenic DT40 cells, we found that apoptosis induction after irradiation was significantly suppressed in Nbs1 knockout cells compared to wild type cells. Because p53 expression was lost in DT40 cells, our observation suggests that Nbs1 might be involved in apoptosis induction pathway that is independent of p53. Our further analysis suggested that NBS1 regulates not only early stage of DNA damage signaling but also late stage triggering apoptosis.